Neural control of the cardiac system depends on the opposing actions of the sympathetic and parasympathetic nervous systems. The sympathetic system is excitatory for beat rate and cardiac output, and dysregulation of sympathetic drive has been linked to a number of human disorders including hypertension and heart failure. The ability to devise new approaches for the treatment of these disorders requires an understanding of the mechanisms that control sympathetic output. These mechanisms take place at the level of sympathetic neurotransmission onto cardiac cells and the regulation of activity levels of ganglionic sympathetic neurons. While sympathetic neurons form excitatory noradrenergic synapses onto cardiac muscle cells, they are also able to synthesize and release acetylcholine, which acts as an inhibitory neurotransmitter for heart muscle and an excitatory neurotransmitter at synapses that the neurons form onto themselves. We will investigate the acute regulation of co- transmission in these neurons and determine the roles of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and their receptors, in coordinating local neurotransmitter properties at neuronal and cardiac synapses. We will use electrophysiology, immunocytochemistry, and perturbation experiments to determine the role of BDNF and NGF in modulating pre- and postsynaptic properties and to examine spatially restricted effects of neurotrophins at sympathetic synapses. We will determine if neurotrophins acutely modulate sympathetic function in vivo. Finally, we will investigate neurotrophic regulation of activity levels and firing properties and will determine how integration of intrinsic and synaptic regulation defines the functional output of the cardiac system. PUBLIC HEALTH RELEVANCE: Heightened sympathetic drive to the heart is linked to a number of pathologies, including sudden cardiac death. In this project we will investigate mechanisms that acutely regulate the level of excitatory and inhibitory transmission in individual sympathetic neurons and test the hypothesis that interactions with target-derived neurotrophic factors can rapidly modulate the pattern of sympathetic activity and the effects of that activity on synaptic function. An understanding of these mechanisms will permit new approaches for developing therapeutics for cardiac pathologies.